OSU Biochemistry and Molecular Biology

Steve Hartson's Laboratory Research

 

    Welcome        Research       Lab Members           CV          Dr. Steve Hartson

 

Our lab is one of many seeking to improve current treatments for cancer.  Our strategy is focused around a cellular protein called “Hsp90,” which stands for “heat shock protein 90.” 

 For reasons that are poorly understood, cancer cells need more Hsp90 than normal cells.  This makes cancer cells very vulnerable to small compounds that attack Hsp90.

 Our lab studies these small compounds and how they work.  We are trying to try and figure out how these drugs kill cancer cells, why they don’t kill normal cells, and whether other drugs work the same way. 

 We’re also doing some speculative out-of-the-box stuff too, but that’s a story for another day…

 The importance of Hsp90 and Hsp90 inhibitors.

 Hsp90 inhibitors are predicted to be effective against several prevalent human cancers.  This prediction is based upon their ability to indirectly compromise several prominent Hsp90-dependent human oncoproteins (e.g., the estrogen and androgen receptors, Bcr-Abl, and Her-2/neu).  In addition to their potential as front-line chemotherapeutics, Hsp90 inhibitors also have potential as adjuvants to traditional chemotherapies (1, 2). 

Moreover, Hsp90 inhibitors may be especially promising against cancers that have acquired resistance to chemotherapy.  Hsp90 supports a broad and diverse panel of human oncoproteins.  Thus, it is widely anticipated that human cancers will less easily evolve resistance to anti-Hsp90 drugs than to traditional one-target drugs (3-5).    

For these reasons, Hsp90 inhibitors hold promise in addressing the half-million cancer deaths that occur in this country each year(6).  Hsp90 inhibitors also hold promise in the treatment of autoimmune diseases, transplant rejection, and neurodegeneration (7-10).

Reflecting their importance, small-molecule Hsp90 inhibitors are moving steadily through early clinical trials, with many trials in progress or pending [http://clinicaltrials.gov/].   Additionally, ongoing high-throughput drug-screening projects and rational drug-design initiatives are yielding literally hundreds of new candidate Hsp90 inhibitors that need to be evaluated [e.g., (11)].

 The studies we propose will address three knowledge gaps that are slowing the deployment of anti-Hsp90 chemotherapies:

(i) A better understanding of Hsp90's role in cancer cells is needed in order to rationally decide which cancers should be treated via Hsp90 inhibition. 

(ii)  More efficient methods are needed to evaluate new candidate Hsp90 inhibitors, and to assess their mechanisms of action.  

(iii)  More knowledge of these compounds' structure-activity relationships is needed in order to guide rational drug design efforts.

 We will address the first knowledge gap by comparing and contrasting Hsp90's roles in cancer cells vs. normal cells.  Cancer cells are more vulnerable to Hsp90 inhibitors than normal cells, and aggressive primitive cancer cells are particularly vulnerable (12).  However, the basis of this selective tumoricidal activity is unknown. 

Most Hsp90 studies focus on the fine atomic details of Hsp90, or they examine Hsp90's roles in supporting one specific protein or an individual cellular pathway.  These proteins are often touted as the mechanism underlying the anti-cancer activity of Hsp90 inhibitors.  However, many of these proteins are specific to certain cancers, but they are not expressed in others.  Thus, they cannot explain the broad anti-tumor activity of Hsp90 inhibitors.  Moreover, many of these Hsp90-dependent proteins are not oncoproteins at all, but rather play essential roles in normal cells.  Thus, current models to explain the efficacy of Hsp90 inhibitors are largely conjectural, and often contentious.

The selective tumoricidal activity of Hsp90 inhibitors strongly suggests that cancer cells have needs for Hsp90 function that differ from those of normal cells.  Thus, we will identify the downstream targets of Hsp90 inhibition in leukemia cells.  We will also determine how Hsp90's roles in normal cells differ from those played in cancer cells.  Achieving Aims 1&3 will illuminate the basis of the selective tumoricidal activities of Hsp90 inhibitiors, and will facilitate the rational deployment of anti-Hsp90 chemotherapies.

We also will identify, validate, and deploy peptide biomarkers of Hsp90 inhibition.  We will do this using two structurally dissimilar, but well validated, Hsp90 inhibitors.  Achieving this Aim will distinguish the bona fide biological fingerprint of Hsp90 inhibition from other off-pathway drug effects.

We will also address a significant bottleneck in the development, assessment, and deployment of new Hsp90 inhibitors.  Several hundred candidate small molecules await in vivo validation as Hsp90 inhibitors.  Currently, this will require innumerable Western blot assays.  For each compound, six to twelve different Hsp90-regulated proteins will need to be assayed by blotting.  Each individual compound will need to be assessed via a time course, a dose response curve, and technical and biological replicates.  These assays will be slow, manpower-intensive, cannot be automated, and will be very costly.  Moreover, they must be quantified by densitometry, creating another manual step and adding a degree of subjectivity.   

In contrast, mass spectrometers are currently capable of identifying and quantifying dozens to thousands of proteins in single-pass assays.  Due to this power, they have become nearly ubiquitous in basic research and in the pharmaceutical industry.  Achieving Aim 1 will deliver a panel of validated peptide biomarkers for Hsp90 inhibition that is sorely needed to assess the large pipeline of candidate Hsp90 inhibitors. 

We will also evaluate a new candidate Hsp90 inhibitor to determine if it shows the in vivo hallmarks of an Hsp90 inhibitor.  This will validate or refute that drug as a new flagship Hsp90 inhibitor, potentially providing a new set of structure-activity relationships, and new insights regarding its impacts on living cells.

 

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